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Salts or Co-Crystals of 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol

a technology of dimethylamino-1 ethyl-2-methylpropyl and cocrystal, which is applied in the field of salt or cocrystal of 3(3dimethylamino1ethyl2methylpropyl)phenol, can solve the problems of undesirable variations, rapid onset of analgesic action, and detrimental to patient complian

Active Publication Date: 2012-01-26
GRUNENTHAL GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a new compound, 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, in a solid form suitable for oral administration. This compound has advantages over previous forms, such as increased solubility and absorption, and can be controlled released without the need for a delayed-release form. The invention also provides a new salt or co-crystal of this compound with an acid that has a lower solubility in water, which allows for controlled release without the need for a matrix or coating. The new compound and salt have improved bioavailability and can be used in pharmaceutical formulations.

Problems solved by technology

Conventional formulations for oral administration of a 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound such as tapentadol usually lead to rapid release of the active substance in the gastrointestinal tract, thereby leading to a rather rapid onset of its analgesic action.
However, the need for frequent dosing may lead to errors in administration and to undesirable variations in the concentration of the compound in the blood plasma which could be detrimental to patient compliance and the therapeutic benefit, particularly when treating chronically painful conditions.

Method used

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  • Salts or Co-Crystals of 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol
  • Salts or Co-Crystals of 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol
  • Salts or Co-Crystals of 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol

Examples

Experimental program
Comparison scheme
Effect test

example b1-1

Salt or Cocrystal of Tapentadol and (2S,3S)-Dibenzoyl Tartaric Acid

[0220]20 g (0.090 mol) of tapentadol and 16.19 g (0.045 mol) of (+)-(2S,3S) dibenzoyl tartaric acid were dissolved in 400 mL of acetone. The mixture was stirred at room temperature for about 3 hours. The resulting crystalline precipitate was filtered off and dried under reduced pressure (6 mbar) at 40° C. (yield 36.1 g, 100%, melting point (DSC): To=152.5° C., Tp=170.7° C.; 9.7 J / g, To=185.7° C., Tp=188.2° C., 119.1 J / g). 1H-NMR analysis showed a 2:1-stochiometry of tapentadol and (+)-(2S,3S) dibenzoyl tartaric acid.

example b1-2

Salt or Cocrystal of Tapentadol and Sebacic Acid

[0221]125 g (0.56 mol) of tapentadol were dissolved in 700 mL of ethyl acetate. To this solution, 114.21 g (0.56 mol) of sebacic acid were added as a solid in portions. Then, 50 mL of ethyl acetate were added. Subsequently, the resulting suspension was stirred for 15 hours. The resulting crystalline white precipitate was then slowly filtered off and dried at 60° C. under reduced pressure (6 mbar) (yield: 232.96 g, 97.37%, melting point (DSC): To=77.9° C., Tp=81.1° C., 99.5 J / g). 1H-NMR analysis showed a 1:1-stochiometry of tapentadol and sebacic acid.

example b1-3

Salt or Cocrystal of Tapentadol and 1-Hydroxy-2-Naphthoic Acid

[0222]120 g (0.54 mol) of tapentadol were dissolved in 700 mL of 2-propanol. To this solution, 102.02 g (0.54 mol) of 1-hydroxy-2-naphthoic acid were added as a solid in portions. Then, 100 mL of 2-propanol were added. After complete addition, the resulting suspension was stirred for 18 hours. The crystallized brownish precipitate was then filtered off and dried at 50° C. under reduced pressure (6 mbar) (yield: 199.43 g, 89.83%, melting point (DSC): To=114.9° C., Tp=122.7, ° C., 1.0 J / g; To=157.6° C., Tp=159.9° C., 78.3 J / g). 1H-NMR analysis showed a 1:1-stochiometry of tapentadol and 1-hydroxy-2-naphthoic acid.

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Abstract

A salt or cocrystal of 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol (component a) and at least one acid component (b1) or at least one acid component (b2), wherein the salt or cocrystal of component (a) and component (b2) is present in crystalline and / or amorphous form, a pharmaceutical composition comprising said salt or cocrystal, and a method of treating pain in a subject in need thereof by administering an effective amount of said salt or cocrystal.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority from co-pending U.S. provisional patent application No. 61 / 367,159, filed Jul. 23, 2010 and from European patent application no. EP 10 007 672.8, also filed Jul. 23, 2010, the entire disclosure of each of which is incorporated herein by reference.BACKGROUND OF THE INVENTION[0002]The invention relates to a salt or cocrystal of 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol (component a) and at least one acid component (b1) or at least one acid component (b2), wherein the salt or cocrystal of component (a) and component (b2) is present in crystalline and / or amorphous form, a medicament comprising said salt or cocrystal as well as said salt or cocrystal for use in the treatment of pain.[0003]3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol compounds such as e.g. (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, which is also known as tapentadol (CAS no. 175591-23-8) are synthetic, centrally ac...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/137A61P29/00A61K31/455C07C215/54C07D213/80
CPCC07B2200/07C07C55/02C07C55/08C07C55/20C07C57/15C07D291/06C07C63/36C07C65/11C07C215/54C07D239/545C07D275/06C07C63/08C07C69/78C07D213/80C07B2200/13A61K31/455A61K31/137A61P25/04C07C57/145C07C59/255C07C59/245C07C63/06C07C57/44C07C59/08C07C59/11C07C59/105C07C53/126C07C57/12C07C65/03C07C59/285C07C53/08C07C55/06C07C55/10C07C59/265
Inventor GRUSS, MICHAELKRASZEWSKI, MAGDA
Owner GRUNENTHAL GMBH
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